Development of a safe and effective oral form of testosterone has been
inhibited by the rapid hepatic metabolism of nonalkylated androgens. Since
triglycerides are absorbed via lymphatics and bypass the liver, we
hypothesized that a testosterone-triglyceride conjugate (TTC) might allow
for safe and effective oral testosterone therapy. Therefore, we studied
the single-dose pharmacokinetics of oral administration of TTC in rabbits.
Female New Zealand rabbits were administered 2, 4, or 8 mg/kg of TTC in
sesame oil by gastric lavage. Testosterone undecanoate (TU) by gastric
lavage was used as a positive control. Blood was sampled from a catheter
in the auricular artery at 0, 15, 30, 60, 90, 120, 180, 240, 360, 480, and
600 minutes after drug administration. Samples were assayed for
testosterone by a fluoroimmunoassay. Mean serum testosterone, area under
the curve (AUC), and terminal half-life were calculated. Oral TTC
administration resulted in rapid and marked increases in serum
testosterone. Oral TTC resulted in higher maximum serum testosterone
concentrations than oral TU at 8 mg/kg (TTC: 28.6 +/- 7.9 nmol/L vs TU:
11.9 +/- 2.1 nmol/L; P <.001) and 4 mg/kg (TTC: 11.5 +/- 4.2 nmol/L vs TU:
3.6 +/- 1.0 nmol/L; P <.001). In addition, the AUC was 1.8 to 2.6 times
greater for TTC than TU at both doses (P <.05). The terminal half-life for
both TU and TTC was between 3 and 5 hours and was not significantly
different. We conclude that oral TTC is rapidly absorbed from the rabbit
intestine and results in elevated concentrations of serum testosterone.
The absorption of TTC appears to be superior to that of TU; however, the
in vivo persistence of the 2 compounds is similar. TTC may offer an
alternative to the use of TU for oral testosterone therapy. Further
testing of this compound is warranted.